Physical Sciences Inc. (PSI) in collaboration with the University of Connecticut, School of Pharmacy (UConn), proposes to develop an advanced freeze-drying microscopy (FDM) system for determining drug formulation collapse temperature. During the Phase I program PSI will demonstrate the application of Optical Coherence Tomography (OCT) for imaging the 3D structure of product formulations freeze dried in standard product vials. The OCT-FDM system will enable product collapse imaging and collapse temperature determination within relevant pharmaceutical packaging systems, overcoming the limitation of current FDM systems which interrogate thin film product samples. This will eliminate errors in collapse temperature determinations which lead to longer processing times, wasted resources and increased production and drug costs. The development of biological drugs often requires product formulations that must be lyophilized to produce stable products that are stored in vials and can be reconstituted for patient use. The most critical process design parameter is the temperature at which the product undergoes structural collapse during primary drying, the "collapse temperature" Tc. Freeze drying below Tc is necessary to insure elegant appearance, low residual water content and therefore good storage stability, and reconstitution characteristics. FDM is one method currently applied to estimate Tc and it uses 1 - 2 uL liquid product samples frozen between microscope slides resulting in a frozen product thickness of 50 - 100 um. These samples are not representative of samples dried in vials which may have thicknesses of 5 - 50 mm. Thin films have different ice nucleation rates, crystallization tendencies for solutes, frozen product structures and drying rates than in vial freeze drying. Thus, current FDM may not accurately estimate Tc for freeze drying in a container of practical significance. Literature studies suggest that the differences in Tc between current FDM and vial drying are typically several degrees resulting in a 25% increase in drying time for every 20 degree C decrease in product processing temperature. The new OCT-FDM technique will result in more accurate collapse temperature determinations representative of what is observed during production scale drying. Laboratory scale, multi-vial experiments will be performed using drying processes developed based on the product Tc determined using the new system. Product quality (appearance, residual moisture and surface area) will be compared for the different drying processes, validating the use of the OCT-FDM measurement technique. The goal of this R&D program is the development and application of a laboratory tool which enables accurate determination of drug product formulation thermal properties for the development of efficient commercial freeze drying processes. PUBLIC HEALTH RELEVANCE: The purpose of this research is to assess the feasibility of developing a laboratory tool that can provide 3D product structural information during freeze drying and product collapse temperature data in a product/container format that is the same as typically used during laboratory and manufacturing scale freeze drying.